The long-term goal of the proposed research is to understand the molecular pathogenic mechanisms underlying orofacial cleft formation. Orofacial clefts, including cleft lip and cleft palate, are common birth defects that affect approximately 1 in 700 live births worldwide. Individuals with orofacial clefts undergo extensive surgical, dental, speech and psychological therapies that usually last for many years from infancy through the teenage years. Despite the frequent occurrence and extensive medical treatment associated with such birth defects, the causes and the pathogenic processes that lead to cleft lip and/or cleft palate are not well understood. Recent studies of craniofacial development in animal models, particularly in mice, have provided valuable information on the genetic and environmental factors involved in cleft pathogenesis. Indeed, characterization of genes involved in clefting in mice has provided candidate genes for human genetic studies and some of these have been associated with clefting in humans. The Dancer mutant mouse provides a unique tool for studying the etiology of orofacial clefting. Dancer is a semidominant mutation that arose spontaneously in mice. Dancer homozygous mutants have cleft lip and cleft palate. Dancer heterozygous mice show predisposition to clefting: these mutant mice show cleft lip after out crossing to a different genetic background and they exhibit significantly increased susceptibility to teratogen-induced clefting. As the first step toward unraveling the molecular mechanisms of orofacial clefting in the Dancer mutant mice, we propose to identify the Dancer gene through high-resolution genetic mapping, positional cloning, and candidate gene analyses approaches. Once the mutant gene is identified, we will use the Dancer mice as a model to study the complex genetics and gene environment interactions involved in orofacial cleft formation. These studies will greatly increase our understanding of the pathogenic mechanisms underlying orofacial cleft formation and will ultimately lead to better diagnosis and methods of prevention of orofacial clefting.